Summary of the proposed research Loss of physical function is reported in over 40% of the 46 million adults in the United States over the age of 65. Aging-related muscle wasting and weakness, referred to as sarcopenia, is a major contributor to loss of physical function. Sarcopenia is associated with a two-fold increased risk of loss of independence and a four- fold increased risk of mortality. Motor neuron loss and loss of motor neuron connectivity with muscle has been demonstrated in aged individuals as well as preclinical models of aging. Each motor neuron is connected to a group of muscle fibers solely under its control, called a muscle unit. Therefore, motor neurons represent the final common output for the central nervous system by converting descending inputs into forces by activating muscle contraction. The scientific premise of the proposed experiments is that loss of motor neuron connectivity with muscle is a driving force leading to aging-related muscle wasting and weakness and that rescuing this connectivity presents an excellent therapeutic target. Preliminary studies have identified Survival Motor Neuron (SMN) protein as an approach to enhancing motor neuron connectivity in aging mice. The proposed experiments will first determine whether loss of motor neuron connectivity can be prevented or delayed with transgenic SMN overexpression. Aging, transgenic mouse with varying levels of SMN will be compared to determine whether SMN overexpression can prevent or delay loss of motor unit connectivity in aging. The primary comparison for effect of SMN expression level in aging will be quantification of motor unit numbers using longitudinal measures of electrophysiology in vivo. Secondary comparisons will include assessments of activity and grip strength, measures of muscle contractility in vivo, morphological assessments of muscle, motor neurons, and neuromuscular junctions. Second, experiments have been designed to determine whether SMN overexpression, induced after onset of aging-related loss of muscle function, results in improved neuromuscular function in aged mice. Preliminary experiments have shown that RG7800, an orally available, small molecule compound, can cross the blood-brain barrier and effectively induce increased SMN expression in aged mice. Aged mice will be randomized to oral delivery of RG7800 or placebo after onset of muscle weakness. The primary comparison to determine effect will be hindlimb muscle contractility in vivo. Electrophysiology of motor unit function will be performed in parallel to understand the mechanism of effects of SMN overexpression on motor unit connectivity after loss of connectivity has already occurred during aging. Secondary comparisons of efficacy will include morphological assessments of muscle, motor neurons, and neuromuscular junctions. There have been no prior clinical trials in therapies directed at increasing motor unit connectivity in individuals with sarcopenia. These studies will provide preclinical rationale for this target and develop SMN-targeting therapies as a promising strategy for the treatment of sarcopenia.